This application seeks to develop the candidate's scientific growth through a rigorous training plan, within an outstanding scientific environment that has a long tradition in translational vascular research. The candidate's long-term goal is to establish an independent clinical research career studying neurovascular mechanisms of cardiovascular (CV) risk in patients with chronic renal failure (CRF). The incidence of CRF is growing at an alarming rate, and the vast majority of these patients die from CV disease. One major independent risk factor for CV mortality in this population is exercise intolerance and poor physical capacity, the mechanisms of which remain largely unknown. Our preliminary data demonstrate that CRF patients have an exaggerated increase in blood pressure (BP) during isometric and rhythmic exercise, suggesting that abnormal hemodynamic responses may play a role. The goals of this project are to examine the mechanisms underlying the exaggerated BP response during exercise in CRF, and to test the potential benefits of tetrahydrobiopterin (BH4) treatment on neural and vascular responses both during exercise and at baseline. Understanding the hemodynamic mechanisms underlying exercise intolerance will help develop therapeutic targets that are urgently needed to improve physical functioning, quality of life, and ultimately reduce CV mortality in CRF. The BP response during exercise is mediated by a balance between vasoconstrictive forces induced by reflex activation of the sympathetic nervous system (SNS), and vasodilatory forces induced by nitric oxide (NO)-dependent vasodilatation. Conceivably, an imbalance in these vasoconstrictive and vasodilatory responses during exercise could lead to an augmented BP response and contribute to exercise dysfunction by increasing myocardial workload, as well as increase the risk of adverse CV events during physical activity. In aim 1, we will determine if CRF patients have exaggerated reflex SNS activation during exercise by measuring changes in SNS activity during static and rhythmic exercise using microneurography. In Aim 2, we will determine if CRF patients have impaired exercise-induced NO-mediated vasodilation, by measuring changes in brachial artery flow-mediated vasodilatation in response to whole-body exercise. Acute exercise also generates an increase in reactive oxygen species (ROS) that stimulates neural SNS outflow, as well as decreases NO bioavailability. Aim 2b will determine if CRF patients have greater production of ROS (i.e. oxidative stress) during acute exercise that contributes to the exaggerated pressor response. Finally, tetrahydrobiopterin (BH4) is an essential cofactor for endothelial NO synthase that improves endothelial function and BP in animal models of CRF by increasing NO bioavailability. In Aim 3, we will conduct the first pilot trial to test the effects of oral BH4 treatment on SNS overactivity, endothelial dysfunction, and oxidative stress, both at rest and during exercise in CRF patients. We hypothesize that BH4 may be a novel therapeutic agent with potential to impact exercise tolerance, as well as CV morbidity and mortality in patients with CRF.